PROJECT SUMMARY. Excitatory receptors activated by the neurotransmitter L-glutamate mediate most excitatory synaptic transmission in vertebrate nervous systems. In the proposed research the glutamate receptor subtypes activated by N-methyl-D-aspartate (NMDA receptors) will be studied. NMDA receptors are essential for many basic nervous system functions, including learning and development, and are involved in a remarkable range of nervous system diseases, including numerous mental disorders. The long-term objectives of the proposed research are to understand the functional and structural properties of NMDA receptors responsible for their multiple roles in brain function. Possibly because of their involvement in multiple neural systems, NMDA receptors are subject to many forms of physiological regulation. One of the most powerful forms of regulation is block of the ion channel of NMDA receptors by extracellular magnesium ions (Mg2+o). The properties of channel block by Mg2+o are fundamental determinants of NMDA receptor involvement in brain function. Several drugs of pharmaceutical importance also block the channels of NMDA receptors. Interaction of Mg2+o and channel-blocking drugs with NMDA receptors in turn also is highly regulated. In the proposed research, we will investigate several of the mechanisms by which channel block of NMDA receptors is regulated, including: the types of subunits that constitute an NMDA receptor, permeation of the channel by Mg2+o, receptor binding of permeant ions, and inherent voltage dependence of receptor function. We will integrate electrophysiological, computational, molecular, and structural analyses to achieve these objectives. The research will deepen our understanding of NMDA receptor regulation, function, and dysfunction under a wide range of conditions, and provide insight into the relation between the structure and properties of NMDA receptors. DESCRIPTION OF RELEVANCE. Imbalanced NMDA receptor activity has been linked to many nervous system disorders, including schizophrenia, Parkinson's disease, Alzheimer's disease, Huntington's disease, stroke, epilepsy, depression, post-traumatic stress disorder, and bipolar disorder. The improved understanding of NMDA receptors that will be provided by the proposed research has enormous potential to help prevent, and ameliorate the consequences of, many forms of brain dysfunction.